Laboratory Studies

The laboratory evaluation should proceed in a manner to confirm the presence of urinary system disease due to crystal or stone formation. Initially, seek common etiologies because xanthinuria is an extremely rare cause of nephropathy and urolithiasis. Laboratory clues that may suggest the diagnosis of xanthinuria include a radiolucent stone, low serum and urine uric acid levels, or crystal nephropathy of undetermined etiology.

Obtain the following urine studies:

Urinalysis can reveal evidence of crystal nephropathy or urolithiasis, including blood and possibly pyuria. Most laboratories should identify common types of urine crystals.
Obtain urine culture.
Obtain 24-hour urine collection to assess calcium, oxalate, uric acid, and creatinine levels. Uric acid levels are low or undetectable in the hereditary xanthinurias.
If xanthinuria is suspected, identify a laboratory that can accurately measure urine xanthine and hypoxanthine. Determine the type of urine collection (ie, timed, spot) necessary. Xanthine and hypoxanthine levels in the urine in healthy individuals are less than 0.01 µmol per millimole of creatinine. In classic xanthinuria, xanthine and hypoxanthine levels are increased significantly, and the ratio of xanthine to hypoxanthine is approximately 4:1. Urine xanthine levels can approach 1 µmol per millimole of creatinine.

Stone analysis is the most direct method to assist the clinician in making the diagnosis of xanthinuria.

Obtain serum studies as follows:

Serum electrolytes, creatinine, BUN, calcium, magnesium, phosphorus, and uric acid levels are appropriate studies in patients with suspected crystal nephropathy or urolithiasis.
Serum uric acid levels are low or undetectable and suggest the possibility of xanthinuria. Note that xanthinuria is not the only disorder with low serum uric acid levels.
Determine xanthine and hypoxanthine blood levels in patients with suspected xanthinuria. Identifying a laboratory capable of assaying the purines and receiving instructions to properly obtain the specimen is important. In general, plasma concentrations of xanthine and hypoxanthine in healthy individuals are less than 1 µmol and less than 5 µmol, respectively. The possible range of xanthine plasma levels is 10-40 µmol in classic xanthinuria.

Liver, duodenal, or jejunal mucosa biopsy material is used to determine tissue xanthine dehydrogenase deficiency; however, measurement of xanthine dehydrogenase activity is not usually necessary to make the diagnosis of classic xanthinuria.

Imaging Studies

Kidneys, ureters, and bladder (KUB) testing with plain radiography of the abdomen is always performed in patients with suspected urolithiasis. Xanthine stones are radiolucent and are not routinely revealed on KUB testing. Further imaging of the urinary tract is necessary to determine the presence of a xanthine stone.

Intravenous pyelography may reveal recent stone passage or a filling defect in the renal pelvis or ureter, consistent with the presence of a radiolucent stone. The study is also helpful in identifying obstruction of urine flow by a stone.

Renal ultrasonography is sensitive enough to identify large radiolucent stones, though this imaging study may miss smaller stones, generally less than 1 cm. The study can determine the presence of hydronephrosis or crystal nephropathy.

CT scanning and MRI are very sensitive for identifying radiolucent stones throughout the urinary system. However, these imaging studies are more expensive and should be reserved for situations when nephrolithiasis is strongly suspected despite negative renal ultrasonography findings.

Other Tests

An allopurinol challenge may be performed.

Patients with classic xanthinuria type I are deficient in xanthine dehydrogenase, whereas patients with type II have a dual deficiency of xanthine dehydrogenase and aldehyde oxidase. Allopurinol is oxidized to oxypurinol by aldehyde oxidase. In patients with type I, allopurinol is metabolized to oxypurinol, whereas patients with type II do not metabolize allopurinol.

No specific clinical guidelines specify how to perform the allopurinol challenge. Generally, oxypurinol is measured in a 24-hour urine specimen on a standard dose of allopurinol for 3-5 days.^[6]

Before administering allopurinol, identifying a laboratory that is capable of measuring oxypurinol is important.

Pyrazinamide and N -methylnicotinamide are also substrates for aldehyde oxidase and have been used to classify the type of classic xanthinuria.

Mraz et al suggested the following non-invasive approach to diagnose hereditary xanthinuria: (1) Documenting an extremely low serum/urinary uric acid and elevated urinary xanthine; (2) typing using urinary metabolomics; and (3) confirmation by molecular genetics.^[6]

Histologic Findings

Crystalline deposits of xanthine in the renal parenchyma may result in tubular epithelial cell damage, interstitial edema, inflammation, and fibrosis.

Treatment & Management

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